title: Generation of bioartificial heart tissue by combining a three-dimensional gel-based cardiac construct with decellularized small intestinal submucosa.
abstract: The in vitro generation of a bioartificial cardiac construct (CC) represents a promising tool for the repair of ischemic heart tissue. Several approaches to engineer cardiac tissue in vitro have been conducted. The main drawback of these studies is the insufficient size of the resulting construct for clinical applications. The focus of this study was the generation of an artificial three-dimensional (3D), contractile, and suturable myocardial patch by combining a gel-based CC with decellularized porcine small intestinal submucosa (SIS), thereby engineering an artificial tissue of 11 cm² in size. The alignment and morphology of rat neonatal cardiomyocytes (rCMs) in SIS-CC complexes were investigated as well as the re-organization of primary endothelial cells which were co-isolated in the rCM preparation. The ability of a rat heart endothelial cell line (RHE-A) to re-cellularize pre-existing vessel structures within the SIS or a biological vascularized matrix (BioVaM) was determined. SIS-CC contracted spontaneously, uniformly, and rhythmically with an average rate of 200 beats/min in contrast to undirected contractions observed in CC without SIS support. rCM exhibited an elongated morphology with well-defined sarcomeric structures oriented along the longitudinal axis in the SIS-CC, whereas round-shaped and random-arranged rCM were observed in CC. Electric coupling of rCM was demonstrated by microelectrode array measurements. A dense network of CD31⁺/eNOS⁺ cells was detected as permeating the whole construct. Superficial supplementation of RHE-A cells to SIS-CC led to the migration of these cells through the CC, resulting in the re-population of pre-existing vessel structures within the decelluarized SIS. By infusion of RHE-A cells into the BioVaM venous and arterial pedicles, a re-population of the BioVaM vessel bed as well as distribution of RHE-A cells throughout the CC was achieved. Rat endothelial cells within the CC were in contact with RHE-A cells. Ingrowth and formation of a network by endothelial cells infused through the BioVaM represent a promising step toward engineering a functional perfusion system, enabling the engineering of vascularized and well-nourished 3D CC of dimensions relevant for therapeutic heart repair.
authors.affiliation: 1 Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School , Hannover, Germany .
authors.forename: Zlata
authors.initials: Z
authors.lastname: Vukadinovic-Nikolic
authors.forename: Birgit
authors.initials: B
authors.lastname: Andrée
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dorfman
authors.forename: Michael
authors.initials: M
authors.lastname: Pflaum
authors.forename: Tibor
authors.initials: T
authors.lastname: Horvath
authors.forename: Marco
authors.initials: M
authors.lastname: Lux
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.forename: Antonia
authors.initials: A
authors.lastname: Bär
authors.forename: George
authors.initials: G
authors.lastname: Kensah
authors.forename: Angelica Roa
authors.initials: AR
authors.lastname: Lara
authors.forename: Igor
authors.initials: I
authors.lastname: Tudorache
authors.forename: Serghei
authors.initials: S
authors.lastname: Cebotari
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Andres
authors.initials: A
authors.lastname: Hilfiker
mesh_terms: D000818:Animals; D021522:Bioartificial Organs; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape; D055724:Electrophysiological Phenomena / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005782:Gels / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000637:transplantation*; D007421:Intestine, Small / Q000098:blood supply / Q000187:drug effects / Q000637:transplantation*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D034421:Sus scrofa; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D005782:Gels; D011943:Receptors, Adrenergic, beta